Introduction

Bacterial resistance to penicillin was encountered in patients1 within 2 years after mass production of the antibiotic began in 1945.2, 3 Since then, the emergence of antibiotic resistance has been reported against virtually all antibiotics developed to date.4 Organizations such as the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have recognized antimicrobial resistance (AMR) as a global threat.5, 6 The misuse and overuse of antibiotics is a significant driver for increasing antibiotic resistance.4, 7 If the scientific community fails to manage and replenish our antibiotic supply, nearly 10 million extra deaths are predicted by 2050 due to drug-resistant infections.8-10 In a postantibiotic era, many interventions that we currently take for granted will be threatened. These include medical advances that have occurred in general surgery,11 treatment of immunocompromised patients,12 organ transplant recipients,13 and patients with prosthetic implants.14 Importantly, increasing levels of antibiotic resistance are already having a profound impact on the care of patients with cancer.15 End cancer as we know it is a major priority of the Biden Administration16 as well as medical societies,17 but achieving that goal will also require action against drug-resistant microbes.

Infections are common in patients with cancer, and they depend upon effective antibiotics to both prevent and treat bacterial infections. Antibiotic failure in patients with cancer increases the frequency of sepsis, sepsis-related mortality, and sepsis-associated costs of care.18-23 Thus it is not surprising that oncologists have been among the first to point out the clinical impact of increasing antibacterial resistance. For example, a recent study in the United Kingdom reported that 46% of the oncologists in the United Kingdom are worried that chemotherapy as a treatment for cancer will be difficult as a result of drug-resistant infections.24 Optimizing the use of current antibiotics and discovery of novel antibiotics are critically important to protect patients with cancer from antibiotic-resistant infections in the future because antibiotic resistance threatens to undo much of the hard-won progress against cancer.25

Antibiotic resistance is defined as the ability of microorganisms to survive when exposed to antibiotics that usually would kill them or prevent their growth.26 Some of the key factors contributing to antibiotic resistance are misuse of antibiotics in humans and animals, use of antibiotics in animal and food industries, lack of rapid diagnosis procedures, and the presence of antibiotics in the environment.27 Antibiotic resistance can be intrinsic or acquired due to various genetic mechanisms. We have highlighted the major mechanisms of antibiotic resistance in Table 1.28-41 Some mechanisms can lead to antibiotic resistance in 1 or 2 classes of antibiotics, whereas others result in multidrug-resistant (MDR) isolates, which are characterized by exhibiting resistance to ≥3 different classes of antibiotics.42, 43 In 2008, Rice et al designated 6 groups of bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) that were commonly associated with antibiotic resistance in the hospital environment and referred to them as ESKAPE pathogens.44 In this review, we focus on recent updates regarding antibiotic-resistant ESKAPE infections, including risk factors, antibiotic use, management, and prevention of antibiotic resistance in patients with cancer.

TABLE 1. Antibiotic-Resistance Mechanisms in ESKAPE Bacteria RESISTANCE TYPE (Blair 201528) EXAMPLES OF MOLECULAR MECHANISMS (Bax & Griffin 201229) EFFECTED ANTIBIOTICS CLASSES (Kapoor 201730) EXAMPLES OF ANTIBIOTIC-RESISTANT ISOLATES FROM PATIENTS WITH CANCER (REFERENCE) Antibiotic inactivation ESBL-producing K. pneumoniae (Zhang 201631)b Aminoglycoside-modifying enzymes ESBL-producing E. coli (Cornejo-Juarez 201532) CRE K. pneumoniae (Satlin 202733)c Carbapenem-resistant A. baumannii (Bodro 201434) Methicillin-resistant S. aureus (MRSA) (Bodro 201434) Metallo-β-lactamase–producing P. aeruginosa (Toleman 200435) Antibiotic target modification Alteration of the peptidoglycan synthesis pathway Vancomycin-resistant E. faecium (Alatorre-Fernandez et al. 201765) Fluoroquinolone-resistant clinical isolates of E. coli (Conrad 199637) Ribosomal mutations Antibiotic efflux Overexpression of multidrug-resistant pumps Tetracyclines and Fluoroquinolones Efflux pump-overexpressing K. pneumoniae and E. coli (Hamed 201838) Reduced permeability of antibiotic Downregulation or mutations in porin proteins K. pneumoniae with porin deletions (Satlin 201339) Abbreviations: CRE, carbapenem-resistant Enterobacterales-like; ESBL, extended-spectrum β-lactamase. a ESKAPE indicates Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. b ESBLs break down and destroy some commonly used antibiotics, including penicillins and cephalosporins (Centers for Disease Control and Prevention 201940). c CRE-like E. coli and K. pneumoniae develop resistance to the group of antibiotics called carbapenems (Centers for Disease Control and Prevention 201941). The Use of Antibiotics and the Burden of Antibiotic Resistance in Patients With Cancer

Infections are one of the most frequent complications seen in patients with cancer,45 and a patient with cancer has a 3 times greater risk of dying from a fatal infection than a patient without cancer.46 Infections are thought to play a primary or associated role in the cause of death in approximately 50% of patients with hematological malignancies or solid tumors,47 even if drug-resistant infections are rarely recorded as the official cause of death on death certificates.48 Bacteria are the most common cause of infections in patients with cancer.47, 49 Risks of developing an infection include disruption of anatomic barriers,50 surgery,51 chemotherapy-related and radiation-related neutropenia,52 and stem cell transplantation.53 More recently, an increased risk of infection is reportedly caused by toxicity mitigation strategies using newer immunotherapies against cancer.54-56 Under neutropenic conditions, patients with cancer are subjected to prolonged treatment of antibiotics prophylactically and empirically.57, 58 However, widespread and prolonged use of broad-spectrum antibiotics to reduce mortality and morbidity from infections in patients with cancer are likely contributors to the emergence of resistance.59-61 In addition, patients with cancer are vulnerable to health care-acquired infections as a major source of antibiotic-resistant organisms.32, 62, 63 We have summarized several studies in which ESKAPE pathogens were isolated from patients with cancer since 2015 in Table 2.31, 59-62, 64-74 These illustrate the prevalence of MDR in different ESKAPE pathogens and highlight that prior antibiotic exposure and hospital-acquired infections are the major risk factors for developing antibiotic resistance in patients with cancer. For Figure 1, we derived data from the National Healthcare Safety Network (NHSN) 2015 to 2017 adult and pediatric antibiotic resistance reports75, 76 to illustrate differences between the percentage of central line-associated bloodstream infections by ESKAPE pathogens that tested nonsusceptible to selected antimicrobial agents. Vancomycin resistance in E. faecium and fluoroquinolone nonsusceptibility in Escherichia coli appear to be significantly higher in adult oncology patients compared with pediatric patients.

TABLE 2. Antibiotic Resistance in Patients With Cancer: Highlights From the Last 5 Years POPULATION STUDIED RESISTANT MICROORGANISMS RISK FACTORS FOR DEVELOPMENT OF ANTIBIOTIC RESISTANCE INTERPRETATIONS REFERENCE BSI episodes in patients with cancer (January 1995 to May 2015) Enterococcus faecium (EF) Prolonged antibiotic exposure 403 Episodes of EF BSIs from 21,695 positive blood cultures Tedim 201760 Increase in BSIs due to EF infections observed from 2005 to 2015 Hematologic neutropenic patients (July 2009 to July 2012) Enterococcus faecium Ampicillin-resistant EF (AREfm) colonization was detected in 32 of 52 patients (61.4%) Sanchez-Diaz 201664 Levofloxacin extended prophylaxis Multidrug-resistant (MDR) clones of AREfm in intestine of patients with cancer increase the development of bacteremia BSIs in patients with hematologic malignancies (January 2008 to December 2012) Enterococcus faecium 58 Episodes of EF BSI episodes from a total of 15,095 blood cultures Alatorre-Fernandez 201765 Vancomycin therapy during the previous 3 mo Higher mortality was associated with vancomycin-resistant isolates BSIs in malignant hematology and oncology patients (2008-2014) Enterococcus faecium Prior antibiotic exposure 96 Patients with EF BSIs were included in the study Xie 202059 Higher 30-d mortality was associated with vancomycin-resistant isolates BSIs in patients with hematologic malignancies (January 2012 to December 2014) Pseudomonas aeruginosa (PA) 64 Patients with PA BSIs were studied Tofas 202061 Prior use of fluoroquinolones PA is an important pathogen in patients who have hematologic malignancies associated with high mortality BSIs in patients with hematologic malignancies and hematopoietic cell transplant recipients (January 2012 to March 2018) Pseudomonas aeruginosa Fluoroquinolone prophylaxis 55 Episodes of PA bacteremia among 51 patients Hakki 201966 Fluoroquinolone prophylaxis was associated with non-susceptibility to meropenem, but not to anti-pseudomonal β-lactams or aminoglycosides BSIs in neutropenic patients with cancer (January 2006 to May 2018) Pseudomonas aeruginosa Prior therapy with piperacillin-tazobactam 1217 Episodes of BSI due to PA across 34 centers in 12 countries Gudiol 202067 Prior anti-pseudomonal carbapenem use The rate of MDR increased significantly over the study period Fluoroquinolone prophylaxis Respiratory infections in patients with lung cancer (September 2017 to October 2018) Klebsiella pneumoniae (KP) KP was identified in 27 of 47 patients who had lung cancer with respiratory infection Ding 202068 51.4% KP isolates were MDR and the dominant strain causing lung infection in patients with lung cancer in the study Patients who had cancer with BSIs, HAIs, and intra-abdominal infections (February to July 2013) Klebsiella pneumoniae History of systemic steroid In total, 230 consecutive cases of KP infection were studied Zhang 201631 Combination antimicrobial therapy 12.6% of hypervirulent KP isolates produced extended-spectrum β-lactamase BSIs in malignant hematology and oncology patients (January 2014 to September 2018) Klebsiella pneumoniae Carbapenem exposure within 30 d before the onset of BSIs 89 patients with KP bacteremia were included in the study Liu 201969 Carbapenem-resistant KP caused more mortality than carbapenem-susceptible KP (55.0% vs 15.9%; P = .001) Patients with cancer (2006 to March 2015) Methicillin-resistant Staphylococcus aureus (MRSA) 21.1% of MRSA was documented from 450 patients reported with S. aureus infection Bello-Chavolla 201870 Protective factors for mortality included catheter removal and initiation of adequate treatment for S. aureus <48 h after positive blood cultures Patients with erythrodermic cutaneous T-cell lymphoma (CTCL) (2012-2016) Staphylococcus aureus Of 50 events, 17 (34%) were due to MRSA Emge 202071 The MRSA prevalence was high in patients with erythrodermic CTC Patients with cancer (June 2014 to March 2016) Methicillin-resistant Staphylococcus aureus 120 Isolates (40 community-acquired and 80 hospital-acquired MRSA) were included in the study Shehata 201972 Patients with community-acquired MRSA showed remarkable ability to acquire MDR after irradiation Patients with cancer (July 2017 to January 2018) Acinetobacter baumannii (AB) 48 AB isolates were recovered from 520 blood samples Wasfi 202073 Carbapenemases were identified as the main mechanism of carbapenem resistance in AB Patients with cancer—outbreak initiated from a single patient (March 2011) Acinetobacter baumannii 66 AB strains (62.3%) were considered infection, and 40 (37.7%) were considered colonization Cornejo-Juarez 202062 Highlighted the threat that represents the transfer of colonized patients with MDR strains between institutions Patients with malignant hematology (January 2014 to June 2015) Acinetobacter baumannii Previous carbapenem exposure 40 Patients with AB bacteremia were identified, accounting for 2.9% (40 of 1358) of bacteremia cases Wang 201774 Patients who had carbapenem-resistant AB infections had significantly longer hospital stays Abbreviations: BLIs, bloodstream infections; HAIs, hospital-acquired infections.

Antibiotic Resistance Is Common in Patients With Cancer. This bar graph displays the percentage of pathogens reported from adult and pediatric central line-associated bloodstream infections (CLABSIs) that tested nonsusceptible (NS) to selected antimicrobial agents in hospital oncology units in the United States from 2015 to 2017. Data for the graph were obtained from the National Healthcare Safety Network 2015 to 2017 adult and pediatric antibiotic resistance reports. *Klebsiella spp. include K. oxytoca and K. pneumoniae. ESCs indicates extended-spectrum cephalosporins (cefepime, cefotaxime, ceftazidime, or ceftriaxone); FQs, fluoroquinolones (ciprofloxacin or levofloxacin); OX/CEFOX/METH, oxacillin, cefoxitin, or methicillin; VRE, vancomycin-resistant Enterococcus.

Antibiotic Resistance Is Related to Unfavorable Outcomes in Patients With Cancer

Antibiotic resistance leads to detrimental effects in patients with cancer, who rely on antibiotics to prevent and treat infections. Although cancer survivorship has increased with the success of modern cancer care, current therapeutic approaches continue to make these patients vulnerable to infections.77-79 A meta-analysis by Teillant et al found that, in postchemotherapy infections, 26.8% of pathogens were identified as resistant to the standard prophylactic antibiotics that had been prescribed. That study forecasted that a reduction in antibiotic efficacy of 30% to 70% would result in nearly 4000 to 10000 additional infections and 500 to 1000 additional deaths per year in the United States among patients who go through chemotherapy for hematological malignancies.15

Multiple studies demonstrate the impact of increasing resistance on outcomes in this vulnerable population.80-82 Bodro et al reported increased persistence of bacteremia (25% vs 9.7%), metastatic infection (8% vs 4%), and early case-fatality rates (23% vs 11%) among patients with cancer who had infections caused by antibiotic-resistant ESKAPE pathogens compared with other bacterial pathogens. Risk factors that were associated with having an antibiotic-resistant infection included comorbidities, prior antibiotic therapy, having a urinary catheter, and a urinary tract source of infection. Those authors identified a wide variety of pathogens, including: methicillin-resistant S. aureus (MRSA), extended-spectrum β-lactamase (ESBL)–producing K. pneumoniae, carbapenem-resistant A. baumannii, carbapenem-resistant and quinolone-resistant P. aeruginosa, and de-repression of chromosomal β-lactamase and ESBL-producing Enterobacter species.34

A study in 2015 found that 58 of 282 deaths (23%) among patients with cancer who required intensive care were caused by hospital-acquired infections. In 51 of those 58 cases (88%), an MDR pathogen was identified. The overall prevalence of MDR pathogens was nearly 40% in microorganisms collected from patients who were admitted to the intensive care unit. Of the identified MDR pathogens, 20% were caused by E. coli (94.4% of these were ESBL producers), 12% were caused by S. aureus (90.6% of these were MRSA), 12% were caused by E. faecium (18.7% were vancomycin resistant), and 6% were caused by A. baumannii (all were MDR).32

In 109 patients with hematological diseases who were undergoing chemotherapy, overall survival at 30 days was analyzed in those who had Gram-negative bloodstream infections (BSIs). In patients who had infections caused by MDR bacteria, survival was significantly lower compared with the survival of those who had infections caused by non-MDR isolates (85.6% vs 55.9%; P < .001).83 In addition, numerous recent studies support the association of antibiotic resistance with unfavorable outcomes in patients with both hematological malignancies and solid tumors.84-88 The impact of resistance is not limited to the adult population. In a tertiary children's hospital from 2010 to 2014, carbapenem-resistant versus carbapenem-susceptible BSI was associated with a longer duration of bacteremia (mean, 3.8 vs 1.7 days), a higher risk for intensive care unit hospitalization (44.4% vs 10.1%), and a higher mortality rate (33% vs 5.8%) in patients with hematological malignancies and after hematopoietic stem cell transplantation.89

Infections with antibiotic-resistant bacteria have been studied less in patients with solid tumors than in those with hematological malignancies.